| Background and Objective:Nitroglycerin(NTG)has been used for the treatment of ischemic heart disease and congestive heart failure(CHD)more than 130 years,and up to now NTGis still an important drug commonly used in cardiovascular medicine. However ,many scholars find that chrinic NTG treatment will result in development of tolerance, ie, the reduction in effect or the requirement for higher doses to maintain it's efficiency,which is a major factor limiting the efficacy of this drug.Although in the past decades,many studies have demonstrated that NTG therapy leads to complex interactions between the vascular endothelial cells, neurohonnones and free oxygen radicals, the exact mechanism(s) of tolerance remain unclear.But now the concept focus on the following facts,including of neuroendocrine system activation, oxidative stress, unusual biotransformarion of NTG,nitric oxide(NO) signal convection system dysfunction, endothelial functional disorder .And vascular superoxide anion( O2-) and nitrite production increasing and NO content or efficiency decreasing and endothelial nitric oxide synthase(eNOS) being a dysfunctional state- uncoupled NOS,the scond messenger cyclic guanosine monophosphate(cGMP) hydrolysis, reduced form of nicotinamide-adenine dinucleotide phosphate(NAD(P)H), phosphodiesterase(PDE) and endothelin-l(ET-l) production increasing, which are the hot points of the researchs on NTG tolerance. So it is belived that if the above unsual factors can beattenuated,NTG tolerance could be modified and/or prevented. Thus, we designed the present study to investigate the effect of benidipine hydrochloride, one of the dihydropyridine calcium channel blocker (CCB), on the development of NTG tolerance and to search for it's mechanisms.Methods:Benidipine Hydrochloride was purchased from Huaxia Pharma Company limited.NTG patch (16 mg / patch) was purchased from Zhuhai Schwarz Phama Company limited. Sprague-Dawley (SD) rats weighting 300g-350g were provided by the Henan Province Experimental Animal Center. All rats were divided to 2 groups according to the time when Benidipine Hydrochloride was used. In the first group ,Benidipine Hydrochloride was used for 2 week;In the second group Benidipine, Hydrochloride was used for 6 weeks. There was four subgroups in every group and how to consist of the subgroups is the same in two groups.The specific method is that a total 32 SD rats were divided into 4 subgroups at random/DControl subgroup(C subgroup,n=8):No drugs were used,but patches without drugs were applied to the rat and 2~3ml Saline was gaved to every rat by gavage.(2)Benidipine Hydrochloride subgroup (B subgroup,n=8): 6mg / kg Benidipine Hydrochloride,which was involved in 2~3ml Saline , was given to every rat by gavage .And patches without drugs were applied to the rats (3) NTG subgroup (n=8):NTG tolerance animal model was prepared.The region between scapulae was shaved and NTG patch (0.05mg/h) was applied to the skin.The treatment period started between 8 AM and 9 AM and NTG patch was changed each morning.The NTG patches were used for the last three days before the rats were put to death. And 2~3ml Saline was given to every rat by gavage. (4)NTG plus Benidipine Hydrochloride subgroup(NTG+B subgroup,n=8): 2~3ml Saline,which included 6 mg / kg Benidipine Hydrochloride, was given to every rat by gavage and simultaneously NTG patches treatment were used by the same method as which was used in NTG subgroup. Rats were killed and aortas were removed.Part of the aortas was cut into 3~5mm vascular ring.The arota rings were suspended in tissue bath,which was filled with the 37 Kreb's solution and the solution was bubbled with 95%O2 + 5%CO22.Rings were left 45-60 mininutes before being furthertested-Changes in isometric tension were recorded with HN-79 transducer and LMS-2B biograph,and contractions were initiated with 10-6mol/L Norepinephrine. Then with the different density,the maxiam relaxtion response and the density-effect curve were drawed. And the rest aortas were frozen for further measuring the vascular... |
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